Identification of a Sjögren's syndrome susceptibility locus at OAS1 that influences isoform switching, protein expression, and responsiveness to type I interferons.

Sjögren's syndrome (SS) is a common, autoimmune exocrinopathy distinguished by keratoconjunctivitis sicca and xerostomia. Patients frequently develop serious complications including lymphoma, pulmonary dysfunction, neuropathy, vasculitis, and debilitating fatigue. Dysregulation of type I interferon (IFN) pathway is a prominent feature of SS and is correlated with increased autoantibody titers and disease severity. To identify genetic determinants of IFN pathway dysregulation in SS, we performed cis-expression quantitative trait locus (eQTL) analyses focusing on differentially expressed type I IFN-inducible transcripts identified through a transcriptome profiling study. Multiple cis-eQTLs were associated with transcript levels of 2'-5'-oligoadenylate synthetase 1 (OAS1) peaking at rs10774671 (PeQTL = 6.05 × 10-14). Association of rs10774671 with SS susceptibility was identified and confirmed through meta-analysis of two independent cohorts (Pmeta = 2.59 × 10-9; odds ratio = 0.75; 95% confidence interval = 0.66-0.86). The risk allele of rs10774671 shifts splicing of OAS1 from production of the p46 isoform to multiple alternative transcripts, including p42, p48, and p44. We found that the isoforms were differentially expressed within each genotype in controls and patients with and without autoantibodies. Furthermore, our results showed that the three alternatively spliced isoforms lacked translational response to type I IFN stimulation. The p48 and p44 isoforms also had impaired protein expression governed by the 3' end of the transcripts. The SS risk allele of rs10774671 has been shown by others to be associated with reduced OAS1 enzymatic activity and ability to clear viral infections, as well as reduced responsiveness to IFN treatment. Our results establish OAS1 as a risk locus for SS and support a potential role for defective viral clearance due to altered IFN response as a genetic pathophysiological basis of this complex autoimmune disease.

Brief Report: Patients With Primary Sjögren's Syndrome Who Are Positive for Autoantibodies to Tripartite Motif-Containing Protein 38 Show Greater Disease Severity.

OBJECTIVE: Autoantibodies reactive with Ro52 (tripartite motif-containing protein 21 [TRIM21]) are detected in 70% of patients with primary Sjögren's syndrome (SS). TRIM21 belongs to a 34-member C-IV family of TRIM proteins. Although autoantibodies against other TRIM proteins within the C-IV family have been detected in the sera of patients with primary SS, their clinical relevance remains unclear. This study was undertaken to investigate the frequency of anti-TRIM38 in patients with primary SS and evaluate its association with various clinical measures of the disease. METHODS: Serum samples from patients with primary SS (n = 235) and controls (n = 50) were analyzed for reactivity with in vitro-transcribed and -translated (35) S-methionine-labeled TRIM38 protein. The associations of anti-TRIM38 with various laboratory and clinical measures of primary SS were evaluated. Reactivity of anti-TRIM38 with different structural domains of TRIM38 was analyzed. Affinity-purified anti-TRIM38 antibodies were used to immunoprecipitate TRIM21. RESULTS: TRIM38-reactive autoantibodies were detected in the sera of 24 of the 235 patients with primary SS and 2 of the 50 controls. Anti-TRIM38 positivity was significantly associated with the presence of anti-Ro60, anti-Ro52, anti-La, rheumatoid factor, and hypergammaglobulinemia. Clinically, anti-TRIM38 was associated with significantly higher ocular surface staining scores, lower Schirmer's test scores, and minor labial salivary gland biopsy focus scores of ≥3.0. Anti-TRIM38 antibodies mainly recognized the cortactin-binding protein 2 (CortBP-2; amino acids 128-238) and the B30.2/SPRY (amino acids 268-465) domains on TRIM38. Affinity-purified antibodies to TRIM38-CortBP-2 and TRIM38-B30.2/SPRY domains reacted with TRIM21. CONCLUSION: Our data demonstrate that anti-TRIM38 specificity arising in a subset of patients with primary SS is associated with increased severity of the disease.

Bone grafting: history, rationale, and selection of materials and techniques.

In the 100-year history of bone replacement in the human body for different purposes, a wide variety of surgical approaches and materials have been used. The techniques and materials selected significantly affect the outcome of bone replacement procedures in terms of bone formation volume and the quality and amount of vital bone. The choices facing the dental surgeon at the time of extraction, ridge augmentation, or sinus graft are wide-ranging. When choosing a bone graft material the surgeon should consider its ultimate effect on healing patterns in and around the alveolar bone at the endpoint of the procedure. As this article concludes, a better understanding of the materials and the results that can be predictably achieved with them can be valuable to the appropriately trained surgeon when preparing for these procedures.

Histomorphometric evaluation of a calcium-phosphosilicate putty bone substitute in extraction sockets.

The objective of this study was to evaluate bone regeneration in 24 sockets grafted with a calcium phosphosilicate putty alloplastic bone substitute. A core was obtained from 17 sockets prior to implant placement for histomorphometry at 5 to 6 months postextraction. Radiographic analysis during the same postextraction healing period showed radiopaque tissue in all sockets. Histomorphometric analysis revealed a mean vital bone content of 31.76% (± 14.20%) and residual graft content of 11.47% (± 8.99%) after a mean healing period of 5.7 months. The high percentage of vital bone in the healed sites in combination with its timely absorption rate suggest that calcium phosphosilicate putty can be a reliable choice for osseous regeneration in extraction sockets.

Variants at multiple loci implicated in both innate and adaptive immune responses are associated with Sjögren's syndrome.

Sjögren's syndrome is a common autoimmune disease (affecting ∼0.7% of European Americans) that typically presents as keratoconjunctivitis sicca and xerostomia. Here we report results of a large-scale association study of Sjögren's syndrome. In addition to strong association within the human leukocyte antigen (HLA) region at 6p21 (Pmeta = 7.65 × 10(-114)), we establish associations with IRF5-TNPO3 (Pmeta = 2.73 × 10(-19)), STAT4 (Pmeta = 6.80 × 10(-15)), IL12A (Pmeta = 1.17 × 10(-10)), FAM167A-BLK (Pmeta = 4.97 × 10(-10)), DDX6-CXCR5 (Pmeta = 1.10 × 10(-8)) and TNIP1 (Pmeta = 3.30 × 10(-8)). We also observed suggestive associations (Pmeta < 5 × 10(-5)) with variants in 29 other regions, including TNFAIP3, PTTG1, PRDM1, DGKQ, FCGR2A, IRAK1BP1, ITSN2 and PHIP, among others. These results highlight the importance of genes that are involved in both innate and adaptive immunity in Sjögren's syndrome.

A prospective, randomized, controlled, multicenter evaluation of extraction socket preservation comparing two bovine xenografts: clinical and histologic outcomes.

The aim of this prospective, randomized, controlled, multicenter study was to evaluate and compare the histologic and histomorphometric aspects of extraction sockets grafted with two commercially available bovine bone xenografts: Endobon (test group) and Bio-Oss (control group). The study was designed to ensure that baseline variables between groups were as similar as possible to allow for a direct comparison of graft healing characteristics. Thirty-eight patients contributed 62 augmented extraction sites to the study. All sites were grafted with one type of bovine bone mineral and covered with a resorbable collagen membrane for 6 months of healing prior to implant placement surgery. The histologic outcomes between the two treatment groups are similar, with de novo bone (mean ± SD) for the test group at 28.5% ± 20% and for the control group, 31.4% ± 18%. Histologic specimens also include membrane remnants. All but two implants integrated successfully after 1 year of follow-up. This investigation provides support for the efficacy of bovine bone xenograft for socket preservation when subsequent implant placement is planned.

Theoretical model for bone graft success.

Theoretical assumptions must correlate with clinical efficacy and good surgical outcomes to be of value to clinicians and patients. This article examines several common assumptions regarding the use of bone marrow aspirate to enhance bone grafting procedures. Contrary to these assumptions, evidence-based research suggests the following: (1) No more than 4 mL of bone marrow should be aspirated from a single donor site. Aspiration of more than that amount does not substantially increase the number of progenitor cells harvested but instead dilutes the concentration of progenitor cells with other nucleated cells from peripheral blood. (2) Bone marrow aspirate should not be concentrated using centrifuge technology. Rather than isolating desired cells, centrifuging concentrates all nucleated cells, increasing the overall metabolic activity to the detriment of the desired cells. (3) Increasing the volume of graft material brought to a graft site has the unwanted effect of increasing the diffusion distance for oxygen and nutrients and may lead to graft necrosis. (4) Histomorphometric analysis is the most effective method of evaluating bone graft outcomes because only such analysis allows for quantification of the percentage of bone and viable cells within a bone core biopsy.

Enhancing extraction socket therapy with a biphasic calcium sulfate.

Studies have shown that tooth extraction results in loss of bone volume, which compromises dental implant placement. Prevention of site collapse at the time of extraction is recommended. In this 4-month case series, 40 patients were treated with an innovative biphasic calcium sulfate graft, demonstrating its ability to preserve or augment socket volume and resorb in the time period desired between extraction and implant placement. Some representative samples were retrieved at the time of implant placement and evaluated histologically and morphometrically for vital bone formation.

Antral membrane elevation using a post graft: a crestal approach.

The crestal approach to elevating the antral membrane by a resorbable StemVie post is a modification of the sinus lift technique. This technique can add 4-10 mm of bone height for severely atrophic ridges in areas that are difficult to access through a lateral window. The procedure is minimally invasive, simple, and predictable, and has less postoperative morbidity due to smaller flap design and minimal osteotomy. If sufficient alveolar bone is present for stabilization, an implant can be placed simultaneously with an antral elevation and graft. The StemVie post resorbs completely and is replaced by the patient's own bone. Healing is enhanced with the addition of bone marrow aspirate and/or peripheral venous blood to the StemVie post graft. The graft will absorb the blood or the marrow, allowing them to infiltrate through the porosity present in the graft. Bone marrow aspirate aids in healing with the addition of precursor osteoblastic stem cells, cytokines, and growth factors, while peripheral blood supplies mostly cytokines and growth factors.

Monocytes: super cells for bone regeneration.

Monocytes are progenitor cells that lead the inflammatory cascade reaction responsible for guiding revascularization and regeneration of tissue at injury sites. They do this by secreting inductive cytokines responsible for endothelial cell migration. When released into the peripheral blood, monocytes enter tissues and become macrophages. Monocytes also trigger the body's defense mechanism against microbial invasion by lysing and removing cell debris and dead tissue. The aim of this article is to explain the role of monocytes in the processes of bone healing and regeneration and describe their interaction with stem cells and other entities. Results of a pilot histomorphometric study in which concentrated monocytes were combined with demineralized allograft material to augment implant-placement sites in 2 patients also are presented.

Beta-tricalcium phosphate/type I collagen cones with or without a barrier membrane in human extraction socket healing: clinical, histologic, histomorphometric, and immunohistochemical evaluation.

The aim of this study was to investigate the healing of human extraction sockets filled with ß-tricalcium phosphate and type I collagen (ß-TCP/Clg) cones with or without a barrier membrane. Twenty patients were divided in two groups: (A) ß-TCP/Clg non-membrane and (B) ß-TCP/Clg + barrier membrane. Clinical examination and biopsies from the grafted sites were collected 9 months later. Bone samples were analyzed using histomorphometry and immunohistochemistry. The horizontal dimension of the alveolar ridge was significantly reduced 9 months after socket preservation in the non-membrane group. There was bone formation with no significant differences between the two groups in the areas occupied by new bone (A = 42.4%; B = 45.3%), marrow (A = 42.7%; B = 35.7%), or residual graft (A = 9.7%; B = 12.5%). Immunohistochemistry revealed osteonectin expression in both groups. Both groups demonstrated sufficient amounts of vital bone and socket morphology to support dental implant placement after the 9-month healing period. A future trial to evaluate the alveolar outcomes at an earlier 6-month time point rather than the 9 months used in this study would be of interest.

Clinical and histomorphometric observations around dual acid-etched and calcium phosphate nanometer deposited-surface implants.

PURPOSE: The objective of this study was to compare the clinical and histologic peri-implant parameters of a nano-calcium phosphate (CaP)-coated dual acid-etched (DAE) implant (n = 7) to those of an uncoated DAE implant (n = 7). MATERIALS AND METHODS: The study included seven dogs who received implants bilaterally in edentulous mandibular areas; in the right side, procedures were performed 8 months after procedures in the left mandible. Clinical parameters were measured prior to euthanasia (8 months after the second set of implants was placed), followed by histologic nondecalcified processing for morphometric evaluation. Bone-implant contact (BIC), crestal bone resorption (CBR), intrabony defect (IBD), and bone area fraction (BAF) were measured. Analysis of variance with repeated measures and a two-tailed Pearson correlation test were applied. RESULTS: Probing depth, Bleeding Index, and keratinized mucosal height were stable in both groups; there was a significant improvement in probing depths with time (P = .014). Morphometric measurements showed BIC from 75% to 89% in both groups at 8 and 16 months. The nano-CaP-coated group (n-CaP) showed a significant increase in BIC over time when compared to the DAE group (P = .02). Crestal bone level was maintained in both groups with average resorption of 1.4 to 1.5 mm at the n-CaP implants and 1.1 to 1.2 mm at the DAE implants at 8 and 16 months, respectively. Mean IBD values were 0.88 to 1.18 mm at the n-CaP implants and 0.65 to 0.66 mm at the DAE implants at the respective periods. CONCLUSIONS: Within the limitations of this study, both the DAE and the n-CaP-surface implants showed successful osseointegration and functional soft and hard tissue adaptation. Except for the significant increase in BIC around the n-CaP implants over time, both showed similar clinical and histologic findings.

The crestal approach: antral membrane elevation via a post graft.

The crestal approach to elevating the antral membrane by a resorbable StemVie Post is a modification of the sinus lift technique. This technique can add 4 to 10 mm bone height for severely atrophic ridges in areas that are difficult to access through a lateral window. The procedure is minimally invasive, simple, predictable, and has less postoperative morbidity because of smaller flap design and minimal osteotomy. If sufficient alveolar bone is present for stabilization, an implant can be placed simultaneous with antral elevation and graft. The StemVie Post completely resorbs and is replaced by the patient's own bone.

The correlation of bone mineral density and histologic data in the early grafted maxillary sinus: a preliminary report.

PURPOSE: : Implant success in the grafted maxillary sinus is dependent on the formation of new vital autogenous bone and its mineral density. Different bone graft materials and graft combinations have been used in the sinus augmentation procedure to support dental implants under occlusal loads. The goal of this study was to determine whether it is possible to observe a direct correlation between bone mineral density and histologic data in the grafted maxillary sinus. Based on the observed histological findings, we propose a bone mineral density classification that has 3 rather than 4 types of bone. MATERIALS AND METHODS: : A total of 15 patients participated in this study, all of which had only 1 sinus grafted. A total of 34 dental implants were placed in the grafted sinuses. In 7 patients, designated as group A, a 50:50 composite ratio of autogenous and allogeneic bone was used to graft the sinuses. Four patients had the sinuses grafted with a 50:50 composite ratio of a naturally occurring marine algae hydroxyapatite graft material and autogenous bone. One patient had the sinus grafted with 100% autogenous bone. In this group of patients, a total of 25 dental implants were surgically placed 14 to 20 weeks after sinus grafting. The implants were restored 12 weeks later. No implant failures were observed over a 52-week period. The last 3 patients, designated as group B, completed implant surgery beyond the 52-week end point of the study for various reasons. They provided a unique opportunity to histologically observe bone maturation at 68, 88, and 260 weeks, respectively. Using cone beam computed tomography (CT) technology and 3D-CT interactive software, bone mineral density in Hounsfield unit values were recorded during different healing time periods. RESULTS: : In all 15 patients, bone mineral density was observed to steadily increase during the 52-week observation period and beyond, as evidenced by the increase in Hounsfield unit values and the formation of new, vital autogenous trabecular bone. CONCLUSION: : Histologic and histomorphometric data demonstrate a definite correlation with the formation of new, vital autogenous trabecular bone and bone mineral density (quality) that permits early loading of implants in the grafted maxillary sinus.

Simultaneous versus two-stage implant placement and guided bone regeneration in the canine: histomorphometry at 8 and 16 months.

AIM: To compare the effect of timing of implant placement and guided bone regeneration (GBR) procedure on osseointegration and newly formed bone at 8 and 16 months. MATERIAL AND METHODS: In seven dogs, four different sites were bilaterally established: (1) an implant placed in a 6-month healed (6m-GBR) bovine bone mineral (BBM) grafted site; (2) a simultaneously placed implant with the grafted BBM (Si-GBR) followed by a membrane coverage; (3) an implant placed in a membrane-protected non-grafted defect; and (4) an implant placement in a naturally healed site (Cont). Histomorphometry was obtained at 8 and 16 months post-implant placement. Bone-implant contact (BIC), crestal bone resorption (CBR), vertical intra-bony (VIB) defect, bone (BAF) and particle (PAF) area fractions, and osteoconductivity (CON) levels were measured. RESULTS: In all sites, BIC ranged between 62% and 79% with no significant differences. PAF ranged from 17% to 27%, with no effect of time. At 8 and 16 months, BAF was significantly smaller at the Si-GBR site when compared with all other sites, CON was significantly greater at the 6m-GBR site, and CBR and VIB were significantly smaller at the 6m-GBR when compared with the Si-GBR sites. CONCLUSIONS: The simultaneous and delayed techniques both showed a similar osseointegration level over time. However, the staged approach showed enhanced newly formed bone, higher osteoconduction around the grafted mineral, less CBR, and smaller vertical bone defect over time compared with the combined approach.

Bone grafting by means of a tunnel dissection: predictable results using stem cells and matrix.

Bone marrow aspirate has been shown to add stem cells, growth factors, and cytokines to bone graft matrices used in bone augmentation sites. The combination of bone marrow aspirate and resorbable scaffold material has a significant osteogenic capability that exceeds that of autogenous bone grafts. This article describes a subperiosteal tunneling technique for applying such grafts to defective sites. Treatment of 2 patients for whom the technique was used to graft 6 deficient sites is described. Histological results and histomorphometric analysis of bone core samples taken from 4 of the 6 grafting sites are also reported. Analysis of the 4 bone cores taken between 4 and 6 months showed a range of 34% to 45% of new bone.

Histologic evaluation of recombinant human platelet-derived growth factor-BB after use in extraction socket defects: a case series.

Recent advancements in the arena of therapeutic molecular enhancement have shown favorable clinical findings for periodontics. However, further studies to optimize clinical outcomes using this technology are warranted. Twelve premolar extraction sockets were assigned randomly for treatment with 0.3 mg/mL recombinant human platelet-derived growth factor (rhPDGF-BB) combined with either a collagen containing anorganic deproteinized bovine bone (xenograft) or beta-tricalcium phosphate (b-TCP). Histologic evaluation of extraction socket healing was performed at 3 months. Histologic findings were similar with b-TCP and the xenograft, having 21% and 24% vital bone, respectively. The use of rhPDGF-BB with either b-TCP or a xenograft resulted in uneventful socket healing. At reentry, all implants were placed without the need for further grafting, and 100% implant success was recorded at the time of final evaluation (restoration completion).

Evaluation of implants coated with recombinant human bone morphogenetic protein-2 and vacuum-dried using the critical-size supraalveolar peri-implant defect model in dogs.

BACKGROUND: Endosseous implants coated with recombinant human bone morphogenetic protein-2 (rhBMP-2) in a laboratory bench setting and air-dried induce relevant bone formation but also resident bone remodeling. Thus, the objective of this study is to evaluate the effect of implants fully or partially coated with rhBMP-2 and vacuum-dried using an industrial process on local bone formation and resident bone remodeling. METHODS: Twelve male adult Hound Labrador mongrel dogs were used. Critical-size, supraalveolar, peri-implant defects received titanium porous oxide surface implants coated in their most coronal aspect with rhBMP-2 (coronal-load, six animals), or by immersion of the entire implant in a rhBMP-2 solution (soak-load, six animals) for a total of 30 µg rhBMP-2 per implant. All implants were vacuum-dried. The animals were sacrificed at 8 weeks for histometric evaluation. RESULTS: Clinical healing was unremarkable. Bone formation was not significantly affected by the rhBMP-2 application protocol. New bone height and area averaged (± SE) 3.2 ± 0.5 versus 3.6 ± 0.3 mm, and 2.3 ± 0.5 versus 2.6 ± 0.8 mm(2) for coronal-load and soak-load implants, respectively (P >0.05). The corresponding bone density and bone-implant contact registrations averaged 46.7% ± 5.8% versus 31.6% ± 4.4%, and 28% ± 5.6% versus 36.9% ± 3.4% (P >0.05). In contrast, resident bone remodeling was significantly influenced by the rhBMP-2 application protocol. Peri-implant bone density averaged 72.2% ± 2.1% for coronal-load versus 60.6% ± 4.7% for soak-load implants (P <0.05); the corresponding bone-implant contact averaged 70.7% ± 6.1% versus 47.2% ± 6.0% (P <0.05). CONCLUSIONS: Local application of rhBMP-2 and vacuum-drying using industrial process seems to be a viable technology to manufacture implants that support local bone formation and osseointegration. Coronal-load implants obviate resident bone remodeling without compromising local bone formation.

Alveolar ridge augmentation using implants coated with recombinant human growth/differentiation factor-5: histologic observations.

OBJECTIVES: In vitro and in vivo preclinical studies suggest that growth/differentiation factor-5 (GDF-5) may induce local bone formation. The objective of this study was to evaluate the potential of recombinant human GDF-5 (rhGDF-5) coated onto an oral implant with a purpose-designed titanium porous oxide surface to stimulate local bone formation including osseointegration and vertical augmentation of the alveolar ridge. MATERIALS AND METHODS: Bilateral, critical-size, 5 mm, supraalveolar peri-implant defects were created in 12 young adult Hound Labrador mongrel dogs. Six animals received implants coated with 30 or 60 microg rhGDF-5, and six animals received implants coated with 120 microg rhGDF-5 or left uncoated (control). Treatments were alternated between jaw quadrants. The mucoperiosteal flaps were advanced, adapted, and sutured to submerge the implants for primary intention healing. The animals received fluorescent bone markers at weeks 3, 4, 7, and 8 post-surgery when they were euthanized for histologic evaluation. RESULTS: The clinical examination showed no noteworthy differences between implants coated with rhGDF-5. The cover screw and implant body were visible/palpable through the alveolar mucosa for both rhGDF-5-coated and control implants. There was a small increase in induced bone height for implants coated with rhGDF-5 compared with the control, induced bone height averaging (+/-SD) 1.6+/-0.6 mm for implants coated with 120 microg rhGDF-5 versus 1.2+/-0.5, 1.2+/-0.6, and 0.6+/-0.2 mm for implants coated with 60 microg rhGDF-5, 30 microg rhGDF-5, or left uncoated, respectively (p<0.05). Bone formation was predominant at the lingual aspect of the implants. Narrow yellow and orange fluorescent markers throughout the newly formed bone indicate relatively slow new bone formation within 3-4 weeks. Implants coated with rhGDF-5 displayed limited peri-implant bone remodelling in the resident bone; the 120 microg dose exhibiting more advanced remodelling than the 60 and 30 microg doses. All treatment groups exhibited clinically relevant osseointegration. CONCLUSIONS: rhGDF-5-coated oral implants display a dose-dependent osteoinductive and/or osteoconductive effect, bone formation apparently benefiting from local factors. Application of rhGDF-5 appears to be safe as it is associated with limited, if any, adverse effects.

Alveolar ridge augmentation using implants coated with recombinant human bone morphogenetic protein-7 (rhBMP-7/rhOP-1): histological observations.

BACKGROUND: Pre-clinical studies have shown that recombinant human bone morphogenetic protein-2 (rhBMP-2) coated onto purpose-designed titanium porous-oxide surface implants induces clinically relevant bone formation and osseointegration. The objective of this study was to examine the potential of rhBMP-7, also known as recombinant human osteogenic protein-1 (rhOP-1), coated onto titanium porous-oxide surface implants to support vertical alveolar ridge augmentation and implant osseointegration. MATERIALS AND METHODS: Bilateral, critical-size, 5 mm, supraalveolar peri-implant defects were created in six young adult Hound Labrador mongrel dogs. The animals received implants coated with rhBMP-7 at 1.5 or 3.0 mg/ml randomized to contra-lateral jaw quadrants. The mucoperiosteal flaps were advanced, adapted, and sutured to submerge the implants for primary intention healing. The animals received fluorescent bone markers at 3, 4, 7, and 8 weeks post-surgery when they were euthanized for histological evaluation. RESULTS: Without striking differences between treatments, the implant sites exhibited a swelling that gradually regressed to become hard to palpation disguising the implant contours. The histological evaluation showed robust bone formation; the newly formed bone assuming characteristics of the contiguous resident bone, bone formation (height and area) averaging 4.1+/-1.0 versus 3.6+/-1.7 mm and 3.6+/-1.9 versus 3.1+/-1.8 mm(2); and bone density 56%versus 50% for implants coated with rhBMP-7 at 1.5 and 3.0 mg/ml, respectively. Both treatments exhibited clinically relevant osseointegration, the corresponding bone-implant contact values averaging 51% and 47%. Notable peri-implant resident bone remodelling was observed for implants coated with rhBMP-7 at 3.0 mg/ml. CONCLUSIONS: rhBMP-7 coated onto titanium porous-oxide surface implants induces clinically relevant local bone formation including osseointegration and vertical augmentation of the alveolar ridge, the higher concentration/dose associated with some local side effects.